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Ketoconazole is a synthetic antifungal drug used to prevent and treat skin and fungal infections, especially in immunocompromised patients such as those with AIDS. Due to its side-effect profile, it has been superseded by newer antifungals, such as Fluconazole and Itraconazole. It is sold commercially as Nizoral by Janssen Pharmaceutica.
History
Ketoconazole was discovered in 1976 and released in the early 1980s, and was the first available oral treatment of fungal infections.
Usage
Ketoconazole is usually prescribed for infections such as athlete's foot, ringworm, candidiasis (yeast infection or thrush), jock itch.
The sides-effects of Ketoconazole sometimes used to treat non-fungal problems. The decrease in testosterone caused by the drug makes it useful for treating prostate cancer. Another use is the suppression of glucocorticoid synthesis, where it is used in the treatment of Cushing's disease. These side effects have also been studied for use in reducing depressive symptoms and drug addiction, however it has not succeded in either of these roles.
Ketoconazole can be prescribed as a 200 mg pill, a 2% ointment, or 2% shampoo for the treatment of dandruff or seborrhoeic dermatitis, or as a 1% over-the-counter Nizoral shampoo.
Ketoconazole is very lipophilic, which leads to accumulation in fatty tissues. Less toxic, and more effective triazole compounds, fluconazole and itraconazole, has largely replaced ketoconazole for internal use. Ketoconazole is best absorbed at highly acidic levels, so antacids or other causes of decreased stomach acid levels will lower the drug's effectiveness when taken orally.
It is a Pregnancy category C drug because animal testing has shown it to cause Teratogenesis in high dosages. Only two human test cases have been recorded (both during the treatment of Cushing's disease) and no adverse effects were reported, however this is not a broad enough data sample to draw conclusions from.
Method of action
Ketoconazole is imidazole structured, and interferes with the fungal synthesis of ergosterol, the main constituent of cell membranes, as well as certain enzymes. It is specific for fungi, as mammalian cell membranes contain no ergosterol.
As with all azole antifungal agents, ketoconazole works principally by inhibition of an enzyme, cytochrome P450 14-alpha-demethylase (P45014DM). This enzyme is in the sterol biosynthesis pathway that leads from lanosterol to ergosterol. Fluconazole an itraconazole have been found to have a greater affinity to fungal cell membrane than ketoconazole, and thus lower doses of azoles are required to kill fungi.
Sensitive fungi
Ketoconazole inhibits growth of dermatophytes and yeast species (such as Candida albicans). No resistance has been reported.
External links
Janssen Pharmaceutica fungal infections page (http://www.janssenpharmaceutica.be/health_research5_E.asp)
Doctor Fungus Ketoconazole Page (http://www.doctorfungus.org/thedrugs/Ketoconazole.htm)
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